In previous studies, we and others showed evidence for the aberrant re-expression of a series of cell cycle-related proteins in specific vulnerable neuronal populations in Alzheimer disease (AD). That a mitotic cell cycle-related mechanism may play an important role in disease pathogenesis is highlighted by the earlier occurrence of cell cycle proteins compared to abnormal tau in AD and by their appearance at the very earliest prodrominal phase of disease (i.e., mild cognitive impairment). Furthermore, that cell cycle proteins are representative of a true cell cycle, rather than being an epiphenomena of other processes, is evident from evidence showing that there is a true mitotic alteration that leads to DNA replication (i.e., S phase) in neurons in AD. These findings led us to develop a novel hypothesis that neurodegeneration in AD, like cancer, is a disease of inappropriate cell cycle control. In support of this notion, we found that the expression a powerful cell cycle inducer, MYC, drives primary neurons to re-enter the cell cycle and, moreover, that MYC-induced cell cycle re-entry leads to tau phosphorylation. Based on these in vitro findings, we have recently developed a bitransgenic mouse model that inducibly expresses MYC specifically in forebrain neurons (CaMKII-MYC). In our preliminary analysis of these CaMKII-MYC animals, we found that MYC expression in this animal model: 1) drives neurons to enter the cell cycle; 2) causes hyperphosphorylation of tau; 3) leads to accumulation of intraneuronal AB; 4) results in a neurodegenerative (TUNEL) Phenotype; 5) leads to gliosis; and 6) causes major cognitive deficits (Y- maze and MWM). Since the aforementioned pathological and behavioral changes are all synonymous with AD, this mouse may be a very useful model of disease pathogenesis. The goal of this proposal is to further delineate the importance of neuronal cell cycle re-entry using this CaMKII-MYC animal model (Aim 1) and examine the effects of neuronal cell cycle re-entry under A2-rich conditions by analysis of a triple transgenic Tg2576/CaMKII-MYC mice (Aim 2). At the conclusion of these studies, we hope to not only have advanced our understanding of fundamental mechanisms that control neuronal cell cycle, particularly as it applies to AD, but also suggest novel therapies that could be manipulated to either prevent initiation of degeneration or stimulate recovery of damaged neurons in neurodegenerative conditions. Alzheimer disease is the leading cause of dementia in the United States. Recent studies have implicated inappropriate cell cycle re-entry in vulnerable neurons as playing a role in the neuronal loss, pathology, and cognitive impairment that are characteristic of the disease. This proposal will help to clarify the role of cell cycle re-entry in Alzheimer disease by characterizing a novel transgenic mouse model of cell cycle re-entry and delineating the effects of cell cycle re-entry in an amyloid-rich environment.